Openly accessible

Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival

Thomas, Daniel, Powell, Jason A., Green, Benjamin D., Barry, Emma F., Ma, Yuefang, Woodcock, Joanna, Fitter, Stephen, Zannettino, Andrew C. W., Pitson, Stuart M., Hughes, Timothy P., Lopez, Angel F., Shepherd, Peter R., Wei, Andrew H., Ekert, Paul G. and Guthridge, Mark A. 2013, Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival, PLoS biology, vol. 11, no. 3, doi: 10.1371/journal.pbio.1001515.

Attached Files
Name Description MIMEType Size Downloads

Title Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival
Author(s) Thomas, Daniel
Powell, Jason A.
Green, Benjamin D.
Barry, Emma F.
Ma, Yuefang
Woodcock, Joanna
Fitter, Stephen
Zannettino, Andrew C. W.
Pitson, Stuart M.
Hughes, Timothy P.
Lopez, Angel F.
Shepherd, Peter R.
Wei, Andrew H.
Ekert, Paul G.
Guthridge, Mark A.ORCID iD for Guthridge, Mark A. orcid.org/0000-0002-0536-3471
Journal name PLoS biology
Volume number 11
Issue number 3
Article ID e1001515
Total pages 14
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2013
ISSN 1544-9173
1545-7885
Summary The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML) cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in cancer.
Language eng
DOI 10.1371/journal.pbio.1001515
Indigenous content off
Field of Research 06 Biological Sciences
11 Medical and Health Sciences
07 Agricultural and Veterinary Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2013, Thomas et al.
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30132252

Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 15 times in TR Web of Science
Scopus Citation Count Cited 0 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 84 Abstract Views, 1 File Downloads  -  Detailed Statistics
Created: Thu, 21 Nov 2019, 14:07:24 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.